Despite considerable knowledge regarding the etiology of sickle cell disease, effective treatment has been elusive. Modalities for therapy have largely been directed at symptomatology. This disease is a major cause of illness in black populations throughout the world; it is estimated that 1 in 600 black individuals suffer from this disorder and that 8% are heterozygous carriers of the trait. Moreover, an equal number of individuals suffer from sickle cell equivalents (sickle cell-hemoglobin C disease and sickle cell-β-thalassemia) (1).
Since the discovery of the etiology of sickle cell disease in 1949 by Pauling and his colleagues (2), a vast literature has grown in the fields of biochemistry, molecular biology and genetics regarding the mechanisms involved in the aggregation or polymerization of hemoglobin S (“HbS”), the sickling of intact erythrocytes and the inhibition of sickling by other hemoglobins (see review by Bunn) (3).
Despite the voluminous literature, little progress has been made in the treatment of this disabling disorder. The ideal treatment would involve replacement of the gene for βS production with an innocuous substitution. Many laboratories are pursuing this goal, to date none successfully (4). An alternative treatment would involve an oral, readily absorbed, non-toxic agent, capable of entering erythrocytes where it would inhibit gelation of HbS and ultimate sickling of the cells. To date no such agents have been identified.
At present, perhaps the drug used most frequently in the treatment of sickle cell disease is hydroxyurea, a commonly used chemotherapeutic agent (5). Treatment with hydroxyurea depends primarily on induction of the biosynthesis of intracellular hemoglobin F (HbF) (6-11), a hemoglobin known to be effective in inhibiting sickling both in vitro and in vivo. Clinical trials with hydroxyurea have demonstrated a reduction in frequency and severity of painful crises and in transfusion requirements (10-12). Despite the benefits of hydroxyurea therapy, there is concern regarding the consequences of long term use of an anti-neoplastic agent, and treatment is far from optimal.
The present discovery relates to uses of antiviral agents such as acyclovir and valacyclovir to inhibit the aggregation of HbS and the sickling of erythrocytes taken from patients with sickle cell disease both in vitro and in vivo. The low toxicity of the agents at the relatively high concentrations used to treat herpetic infections makes them good agents for the treatment of sickle cell disease.